Understanding tolerance to cell wall–active antibiotics

Dörr, Tobias

doi:10.1111/nyas.14541

Cited by 24 publications

(34 citation statements)

References 290 publications

(642 reference statements)

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“…Therefore, A. baumannii strains in stasis, a relevant physiological state during infection when the cell is known to fortify the cell envelope and slow growth/division 22 , are highly tolerant to lethal meropenem concentrations. While these data agree with current dogma that -lactam-dependent killing is strictly proportional with growth rate 7,23,24 , subsequent analysis revealed that stationary phase A. baumannii cells experience significant cell envelope damage upon Fluorescence intensity measurements were equivalent in treated and untreated cells. Furthermore, fluorescence intensity was higher at the midcell, where the divisome regulates daughter cell formation, suggesting the recovered population had resumed division (Fig 1E).…”

Section: Meropenem Susceptible a Baumannii Strains Are Tolerant Form Spheroplasts And Resume Normal Morphology And Growth Upon Removal Ofsupporting

confidence: 87%

“…However, antibiotic tolerance, a population's ability to survive otherwise toxic levels of transient antibiotic treatment for extended periods, likely acts as a stepping-stone to true resistance [3][4][5] . Antibiotic tolerance is characterized by survival of cell populations in a non-dividing state, where the minimal inhibitory concentration does not change and cells revert to normal growth when the antibiotic is removed, degraded or diluted [6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

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Peptidoglycan recycling contributes to outer membrane integrity and carbapenem tolerance inAcinetobacter baumannii

Islam

Kazi

Kang

et al. 2021

Preprint

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The Gram-negative cell envelope is an essential structure that not only protects the cell against lysis from the internal turgor, but also forms a barrier to limit entry of antibiotics. Some of our most potent bactericidal antibiotics, the β-lactams, exploit the essentiality of the cell envelope by inhibiting its biosynthesis, typically inducing lysis and rapid death. However, many Gram-negative bacteria exhibit “antibiotic tolerance”, the ability to sustain viability in the presence of β-lactams for extended time periods. Despite several studies showing that antibiotic tolerance contributes directly to treatment failure, and is a steppingstone in acquisition of true resistance, the molecular factors that promote intrinsic tolerance are not well-understood. Acinetobacter baumannii is a critical-threat nosocomial pathogen notorious for its ability to rapidly develop multidrug resistance. While typically reserved to combat multidrug resistant infections, carbapenem β-lactam antibiotics (i.e., meropenem) are first-line prescriptions to treat A. baumannii infections. Meropenem tolerance in Gram-negative pathogens is characterized by morphologically distinct populations of spheroplasts, but the impact of spheroplast formation is not fully understood. Here, we show that susceptible A. baumannii clinical isolates demonstrate high intrinsic tolerance to meropenem, form spheroplasts with the antibiotic and revert to normal growth after antibiotic removal. Using transcriptomics and genetics screens, we characterized novel tolerance factors and found that outer membrane integrity maintenance, drug efflux and peptidoglycan homeostasis collectively contribute to meropenem tolerance in A. baumannii. Furthermore, outer membrane integrity and peptidoglycan recycling are tightly linked in their contribution to meropenem tolerance in A. baumannii.ImportanceCarbapenem treatment failure associated with “superbug” infections has rapidly increased in prevalence, highlighting an urgent need to develop new therapeutic strategies. Antibiotic tolerance can directly lead to treatment failure but has also been shown to promote acquisition of true resistance within a population. While some studies have addressed mechanisms that promote tolerance, factors that underlie Gram-negative bacterial survival during carbapenem treatment are not well-understood. Here, we characterized a role for peptidoglycan recycling in outer membrane integrity maintenance and carbapenem tolerance in A. baumannii. These studies suggest that the pathogen limits antibiotic concentrations in the periplasm and highlights physiological processes that could be targeted to improve antimicrobial treatment.

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Section: Meropenem Susceptible a Baumannii Strains Are Tolerant Form Spheroplasts And Resume Normal Morphology And Growth Upon Removal Ofsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Peptidoglycan recycling contributes to outer membrane integrity and carbapenem tolerance inAcinetobacter baumannii

Islam

Kazi

Kang

et al. 2021

Preprint

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“…Despite being a well-known regulator of polymyxin resistance, the PhoPQ two-component system was not previously known to respond or mediate tolerance to carbapenem treatment. As tolerance (and spheroplast formation in particular) is a possible culprit for antibiotic treatment failure (2, 3, 43), our results suggest a potential for combination therapies with histidine kinase inhibitors to increase the efficacy of carbapenems.…”

Section: Discussionmentioning

confidence: 79%

“…PBPs are enzymes that synthesize the cell wall, an essential structure composed mainly of the polysaccharide peptidoglycan (PG). In many well-studied model organisms, PBP inhibition induces cell wall degradation and often subsequent lysis through the action of cell-wall degrading enzymes (collectively referred to as “autolysins”) in a poorly-understood manner (2). While lysis is the canonical response of model organisms like Escherichia coli K12, many susceptible clinical isolates of Gram-negative pathogens (including prominent Enterobacterales clinical isolates like Klebsiella spp .…”

Section: Introductionmentioning

confidence: 99%

High-level carbapenem tolerance requires antibiotic-induced outer membrane modifications

Murtha

Kazi

Schargel

et al. 2021

Preprint

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Antibiotic tolerance is an understudied potential contributor to antibiotic treatment failure and the emergence of multidrug-resistant bacteria. The molecular mechanisms governing tolerance remain poorly understood. A prominent type of β-lactam tolerance relies on the formation of cell wall-deficient spheroplasts, which maintain structural integrity via their outer membrane (OM), an asymmetric lipid bilayer consisting of phospholipids on the inner leaflet and a lipid-linked polysaccharide (lipopolysaccharide, LPS) enriched in the outer monolayer on the cell surface. How a membrane structure like LPS, with its reliance on mere electrostatic interactions to maintain stability, is capable of countering internal turgor pressure is unknown. Here, we have uncovered a novel role for the PhoPQ two-component system in tolerance to the β-lactam antibiotic meropenem in Enterobacterales. We found that PhoPQ is induced by meropenem treatment and promotes an increase in 4-amino-4-deoxy-L-aminoarabinose [L-Ara4N] modification of lipid A, the membrane anchor of LPS. L-Ara4N modifications enhance structural integrity, and consequently tolerance to meropenem, in several Enterobacterales species. Importantly, mutational inactivation of the negative PhoPQ regulatory element mgrB (commonly selected for during clinical therapy with the last-resort antibiotic colistin, an antimicrobial peptide [AMP]) results in dramatically enhanced tolerance, suggesting that AMPs can collaterally select for meropenem tolerance via stable overactivation of PhoPQ. Lastly, we identify histidine kinase inhibitors (including an FDA-approved drug) that inhibit PhoPQ-dependent LPS modifications and consequently potentiate meropenem to enhance killing of tolerant cells. In summary, our results suggest that PhoPQ-mediated LPS modifications play a significant role in stabilizing the OM, promoting survival when the primary integrity maintenance structure, the cell wall, is removed.

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“…Cell wall is the outermost structure of the plant pathogenic fungi and bacteria, which plays important role in maintaining cell shape and integrity. It also maintains normal metabolism, ion exchange, and osmotic pressure in cells [142]. Some marine compounds can inhibit the formation of microbial cell walls, thus suppress the growth or kill the pathogens.…”

Section: Affect Cell Wall Structuresmentioning

confidence: 99%

Screening of Marine Bioactive Antimicrobial Compounds for Plant Pathogens

Zhao

Chen

2021

Marine Drugs

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Plant diseases have been threatening food production. Controlling plant pathogens has become an important strategy to ensure food security. Although chemical control is an effective disease control strategy, its application is limited by many problems, such as environmental impact and pathogen resistance. In order to overcome these problems, it is necessary to develop more chemical reagents with new functional mechanisms. Due to their special living environment, marine organisms have produced a variety of bioactive compounds with novel structures, which have the potential to develop new fungicides. In the past two decades, screening marine bioactive compounds to inhibit plant pathogens has been a hot topic. In this review, we summarize the screening methods of marine active substances from plant pathogens, the identification of marine active substances from different sources, and the structure and antibacterial mechanism of marine active natural products. Finally, the application prospect of marine bioactive substances in plant disease control was prospected.

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Understanding tolerance to cell wall–active antibiotics

Cited by 24 publications

References 290 publications

Peptidoglycan recycling contributes to outer membrane integrity and carbapenem tolerance inAcinetobacter baumannii

Peptidoglycan recycling contributes to outer membrane integrity and carbapenem tolerance inAcinetobacter baumannii

High-level carbapenem tolerance requires antibiotic-induced outer membrane modifications

Screening of Marine Bioactive Antimicrobial Compounds for Plant Pathogens

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